SEPSIS - MENINGITIS - MALARIA Pr. B. Vandercam Consultation Maladies Infectieuses et Tropicales Cliniques Universitaires St-Luc Octobre 2004

Sepsis Focus Absence of focus Purpura fulminans Community acquired sepsis immunocompentent adult Nosocomial sepsis immunocompetent adult IV DU Asplenic (anatomic or functional) Neutropenia Toxic shock syndrome

Working definitions associated with sepsis and related disorders

Source of infection Anamnesis (pets, travel, household, …) Physical examination (purpura, scar …) Blood culture Urine culture RX thorax Echo (scan abdo) obstacle abscess collection Echo cardio

Activated protein C (- 6 %) Corticosteroids (low (HC 200-300 mg/day) - long (5-7d)) Intensive insuline therapy (- 17%) Volume resuscitation (- 15%)

Prior medicare database analyses MEEHAN T. Jama 1997; 278:2080 Mortality increased significantly with delay in first Abx dose > 8 hrs (registration to dose) GLEASON PP. Arch Intern Med 1999, 159:2562 Mortality based on abx (OR) Cephalosporin 1.0 Cephalosporin + mac 0.76 Fluoroquinolone 0.64

Method : review of Medicare database for patients > 65 yrs hospitalized with x-ray confirmed CAP Period reviewed : July ’98 - March ’99 Patients : 13 771 PSI score : III - 47 % IV - 24 %

Results

Skin lesions and systemic infections

Purpura fulminans : treatment Cefotaxime 2 gr q 4 - 6 h or Ceftriaxone 2 gr q 12 h Allergy Vanco 1 gr q 12 h + Aztreonam 2 gr q 6 h or Moxifloxacin 0,4 gr q 24 h or Levofloxacin 0,5 gr q 12 h

Community acquired sepsis - immunocompetent adults Infecting organisms Enterobacteriacae Staph aureus Strept pneumoniae & spp N. meningitidis Bacteroides spp Treatment Cefotaxime or Ceftriaxone Amoxi clav or cefurox + amino

IVDU Infecting organisms Exclude endocarditis Previous antibiotherapy Staph aureus Exclude endocarditis Previous antibiotherapy Treatment Oxacilline 2 gr q 6 h or Vancomycine 1 gr q 12h + Genta 2,5 mg/kg q 12 h

Asplenia Overwhelming sepsis Stand by therapy Antibioprophylaxis Amoxi clav Allergy, travel --> Moxifloxacin, Levofloxacin Vaccination Antibioprophylaxis

Asplenia sepsis Infecting organisms Treatment S. pneumoniae H. influenzae N. meningitidis Capnocytophaga spp Treatment Ceftriaxone or Cefotaxime

Nosocomial *sepsis - immunocompetent adult Infecting organisms Enterobacteriacae S. aureus Strep pneumoniae Bacteroïdes spp P. aeruginosa CNS * readmission - nursing home

Nosocomial sepsis Local epidemiology Colonization Previous antibiotherapy IV line Urinary catheter Invasive procedure

Treatment Vancomycin ? Cefotaxime or Ceftriaxone or Pip/tazo + amino Ceftazidime or Cefepime or Carbapenem + amino

Sepsis neutropenia Infecting organisms Colonization Strepto spp CNS S. aureus Enterobacteriacae P. aeruginosa Colonization Previous antibiotherapy

Neutropenia « Low risk » Amoxi clav 2 gr q 6-8 h + Cipro 750 q 12 h OR Ceftriaxone 2 gr q 12 h + Amikacin 15-25 mg/kg q 24 h

Neutropenia « High risk » Ceftazidime 2 gr q 8 h Cefepime 2 gr q 8 h Pip/tazo 4 gr q 6 h Imipenem 750 mg q 6 h Meropenem 2 gr q 8 h + amino ???

Toxic shock syndrome Infecting organisms Treatment Strepto A, B, C, Staph aureus Treatment Cefazoline 2 gr q 8 h + Clindamycine 600 mg q 8 h

Clinical diagnosis Fever sensitivity 85% Menigism 70% Altered mental status 60% Kernig Sensitivity 5% Specificity 95% Poser la question = y répondre

Case presentation 25-year-old man 2-day history of severe headache, fever, neck stiffness 38,3 °C No rash Normal mental status and neurologic examination Pain on neck flexion but able to flex his neck fully No Kernig and Brudzinski signs

Contraindications of lumbar puncture Known or suspected space-occupying lesions with mass effect  LP deferred until CT scan Severe uncorrected coagulopathy (INR > 1.5) Trombocytopenia (platelet count < 50 000/mm³) Infection at the puncture site (decubitus ulcer) - Glasgow < 13 - Shock

When should a computerized tomography scan precede a lumbar puncture ? Age over 60 years Immunocompromised state History of primary neurologic disease, head trauma, neurosurgery History of seizure within the past week Altered mental status, cilated or poorly reactive pupils, occular palsy and focal neurologic abnormalities Papilledema, bradycardia, irregular respiration History of cancer Suspicion of brain abscess (endocarditis, bacteremia …) Empiric anti infective therapy without delay

CSF examination Gram stain - Ziehl - Ink Culture (bacteria, fungi, brucella, nocardia …) Bacterial antigens if antibiotherapy Gram or culture negative PCR virus + BK Blood culture 60 % + in acute bacterial meningitis

CSF characteristics in selected neurologic conditions

Purpura, petechia  N. meningitidis Cellulitis face  S. aureus H. influ VRS, VRI  S. pneumoniae Parotitis  Mumps Endocarditis  S. aureus Septic arthritis  S. pneumoniae S. aureus Pregnancy  Listeria

Acute meningitis treatment IV line - blood cultures AB + dexa 10 mg within 30 min(*) LP if no contraindication Chest x-ray Delta scan if needed (*) S. pneumoniae : 4 h N. meningitidis : 2 h LCR

Antibiotherapy Listeria : ampi or CTX S. pneumoniae : peni i 10% cef 3 i 1% H. influ :  vaccination

Antibiotherapy dosage Penetration - bactericide - CMI Cefotax 2 gr -(4 gr) q 4h (ratio 25%) Ceftriaxone 2 gr q 12h (ratio 15 - 30%) Ampi 2 gr q 4h (ratio 10 - 15%) Cefepime (ratio 10%) Ceftazidime (ratio 20 - 40%) Cotrimoxazole (ratio 30 - 35%)

Antibiotic therapy in meningitis IV from the beginning to the end … Standard therapy 7 days for N. meningitidis 10 - 14 days for S. pneumoniae (14) - 21 days for L. monocytogenes

Meningitis : child > 3 months - adults < 50 yrs Infecting organisms S. pneumoniae N. meningitidis H. influ L. monocytogenes Treatment Cefotaxime + ampicilline Ceftriaxone + ampicilline

Meningitis : alcoohol - adults < 50 yrs Cellular immune deficiency - Debilitating illness Infecting organisms S. pneumoniae L. monocytogenes N. meningitidis Gram negative bacilli Treatment Cefotaxime + ampicilline Ceftriaxone + ampicilline

Meningitis : HIV /AIDS Infecting organisms C. neoformans S. pneumoniae M. tuberculosis L. monocytogenes T. pallidum N. meningitidis HIV

Meningitis : cerebrospinal fluid shunt Infecting organisms Coag neg staph S. aureus Diphteroids Enterobacteriaceae Treatment Vancomycin + cefta

Meningitis : after cranial or spinal trauma Infecting organisms S. pneumoniae H. influ Treatment Cefotaxime or Ceftriaxone

Meningitis after cranial or spinal trauma (> 4 days) Infecting organisms Enterobacteriaceae S. aureus P. aeruginosa S. pneumoniae Treatment Vancomycin + ceftazidime

People on the move: demographics year 2003 175 million persons live outside of their country of origin (2,9%) of the world's population Population of concern to UNHCR: 21,6 million Refugees 11,7 million Internally displaced persons: 20-30 million Rural to urban migration: 20-30 million/year 1-2 million migrate permanently every year 700 million tourist arrivals/year

Malaria risk pyramid for 1 month of travel without chemoprophylaxis Oceania 1:5 Africa 1:50 South Asia 1:250 Southeast Asia 1:2500 South America 1:5000 Mexico and Central America 1:10 000 01643

Délai d’apparition de malaria selon espèce Schwartz NEJM 2003; 349, 1510

Malaria en Belgique Institut de Santé Publique-Louis Pasteur

Who dies from travelers’ malaria ? USA & Canada (n = 21) Total (%) No chemo 21 100 Dealy seeking care 1 5 Missed by MD 13 62 Lab misdiagnosis 9 43 Mistreatment 11 52 MMWR July 20, 2001 & 1999; 48:SS-1 Kain K et al. CMAJ 2001, 164:654-659

Toute fièvre au retour des tropiques est une malaria jusqu’à preuve du contraire !!

Contribution de certaines anomalies biologiques au diagnostic de la malaria Thrombopénie : 60-85% Si de plus GB  N : VPP : 77% VPN : 92% Leucopénie ou GB N : quasi-constante CRP: 100% (mais très peu spécifique) Précoce Très élevé // à parasitémie et à évolution  VPN très bonne (probable) si CRP N  LDH : (très) sensible : 83-100% peu spécifique : 60%  haptoglobine :  90% des cas VPN élevée de taux N Intérêt potentiel couplé à CRP

Malaria à P. falciparum Règles: Vu la provenance essentiellement africaine des souches isolées en Belgique Hospitaliser si: patient non immun patient immun avec > 2% GR+ et/ou critères de gravité Préférer un traitement à base de quinine (5j ± 2j) si malaria sévère (+ doxycycline)

La parasitémie peut augmenter durant les premières 24h de traitement (action sur points limités du cycle qui continue à évoluer "malgré" le traitement)  Résistance R3 est déterminée à 48h (où diminution de 75% doit être obtenue) La température peut persister pendant 72-96h sans signification péjorative Si haute suspicion de malaria, et GE (-) : répéter 3 - 4 x sur 48h

Traitement de la malaria à P. falciparum sévère Bihydrochlorate de quinine 500 mg IV (dans 250ml glucosé ED) en 4h/ 3x/j pdt 3-7j 10 mg/kg (soit 8mg/kg de quinine base) 3x/j chez enfant N.B.: si origine S. Est Asiatique (ou si malaria sévère ?) dose charge : 20 mg/kg (donc 1 seule fois) ou (dès que possible/début si pas V /peu critères gravité) Sulfate de quinine: 500 mg per os 3x/j pdt 3-7 jours

Doxycycline 200 mg/j puis 100 mg/j pdt 6 j ou + Doxycycline 200 mg/j puis 100 mg/j pdt 6 j ou Clindamycine 600 mg 3-4x/jour pdt 3-7 j (par exemple, si grossesse)

P. falciparum (zone A) - P. vivax, P. ovale (*) Malaria treatment P. falciparum (zone A) - P. vivax, P. ovale (*) Day 1 : nivaquine 600 mg + 300 mg Day 2 : 300 mg Day 3 : 300 mg (*) Primaquine 15 mg q 24 h x 14 days

Malaria treatment P. falciparum Malarone P.O 4 x 3 days (food, milky drink) Quinine sulfate 500 mg q 8 h x 3-7 days + Doxy 100 mg q 12h x 7 days Quinine I.V. 10-20 mg/kg over 4 h in 5% dextrose Quinine I.V. 10 mg/kg over 4 h q 8 h + Doxy 100 mg q 12h or Clinda 10 mg/kg q 8h Qt ! Halofantrine ! Mefloquine 2 weeks